Morphine and other mu opioids mimic and/or modulate the subjective effects of cocaine, possibly reflecting mutual stimulation of mesolimbic dopamine activity Less is known about the capacity of cocaine and related stimulants to modulate the subjective effects of morphine The present study investigated the effects of cocaine, amphetamine and reference drugs, administered alone and combined with morphine, in squirrel monkeys trained to discriminate morphine from vehicle Additional studies determined the ability of opioid and dopamine receptor antagonists to attenuate the effects of morphine and the morphine-like effects of other drugs The effects of morphine were mimicked by the mu opioid agonist fentanyl, but not the delta opioid agonists SNC 80 and BW 373U86 or the kappa opioid agonist U50,488H, and were antagonized by the opioid antagonist naltrexone, but not the dopamine antagonist flupenthixol In a subgroup of monkeys, the effects of morphine also were mimicked b y cocaine, amphetamine and the dopamine transport inhibitor GBR 12909, but not the norepinephrine transport inhibitor talsupram or the serotonin transport inhibitor fluoxetine, and were antagonized by flupenthixol but not naltrexone In these subjects, pretreatment with cocaine or amphetamine enhanced the effects of morphine, whereas in other monkeys pretreatment with either stimulant attenuated morphine's subjective effects The results demonstrated individual differences in morphine-like effects of stimulants that are mirrored by individual differences in their interactions with morphine Furthermore, different mechanisms appear to mediate the subjective effects of morphine and the morphine-like subjective effects of cocaine and amphetamine Such differences could have implications for the management of speedball abuse among individuals who combine stimulants and opioids for ostensibly different reasons (i e , to enhance the subjective state of euphoria or to attenuate the undesi rable effects of the individual drugs) PUBLICATIONS Rowlett JK, Negus SS, Shippenberg TS, Mello NK, Walsh SL and Spealman RD Combined cocaine and opioid abuse From neurobiology to the clinic NIDA Res Mongr 178:55-57, 1998